Machine learning (ML) methods offer opportunities for gaining insights into the intricate workings of complex biological systems, and their applications are increasingly prominent in the analysis of omics data to facilitate tasks, such as the identification of novel biomarkers and predictive modeling of phenotypes. For scientists and domain experts, leveraging user-friendly ML pipelines can be incredibly valuable, enabling them to run sophisticated, robust, and interpretable models without requiring in-depth expertise in coding or algorithmic optimization. By streamlining the process of model development and training, researchers can devote their time and energies to the critical tasks of biological interpretation and validation, thereby maximizing the scientific impact of ML-driven insights. Here, we present an entirely automated open-source explainable AI tool, AutoXAI4Omics, that performs classification and regression tasks from omics and tabular numerical data. AutoXAI4Omics accelerates scientific discovery by automating processes and decisions made by AI experts, e.g. selection of the best feature set, hyper-tuning of different ML algorithms and selection of the best ML model for a specific task and dataset. Prior to ML analysis AutoXAI4Omics incorporates feature filtering options that are tailored to specific omic data types. Moreover, the insights into the predictions that are provided by the tool through explainability analysis highlight associations between omic feature values and the targets under investigation, e.g. predicted phenotypes, facilitating the identification of novel actionable insights. AutoXAI4Omics is available at: https://github.com/IBM/AutoXAI4Omics.

SUMMARY: Haplotype assembly of polyploids is an open issue in plant genomics. Recent experimental studies on highly heterozygous autotetraploid potato have shown that available methods do not deliver satisfying results in practice. We propose an optimal method to assemble haplotypes of highly heterozygous polyploids from Illumina short-sequencing reads. Our method is based on a generalization of the existing minimum fragment removal model to the polyploid case and on new integer linear programs to reconstruct optimal haplotypes. We validate our methods experimentally by means of a combined evaluation on simulated and experimental data based on 83 previously sequenced autotetraploid potato cultivars. Results on simulated data show that our methods produce highly accurate haplotype assemblies, while results on experimental data confirm a sensible improvement over the state of the art. AVAILABILITY AND IMPLEMENTATION: Executables for Linux at http://github.com/Computational Genomics/HaplotypeAssembler. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.

Bioinformatics (2019) doi.10.1093/bioinformatics/btz060 The author apologises for the error.

Computer simulations can be used to study population genetic methods, models, and parameters, as well as to predict potential outcomes. For example, in plant populations, predicting the outcome of breeding operations can be studied using simulations. In-silico construction of populations with pre-specified characteristics is an important task in breeding optimization and other population genetic studies. We present two linear time Simulation using Best-fit Algorithms (SimBA) for two classes of problems where each co-fits two distributions: SimBA-LD fits linkage disequilibrium and minimum allele frequency distributions, while SimBA-hap fits founder-haplotype and polyploid allele dosage distributions. An incremental gap-filling version of previously introduced SimBA-LD is here demonstrated to accurately fit the target distributions, allowing efficient large scale simulations. SimBA-hap accuracy and efficiency is demonstrated by simulating tetraploid populations with varying numbers of founder haplotypes, we evaluate both a linear time greedy algoritm and an optimal solution based on mixed-integer programming. SimBA is available on http://researcher.watson.ibm.com/project/5669.

BACKGROUND: Simulation of populations with specified characteristics such as allele frequencies, linkage disequilibrium etc., is an integral component of many studies, including in-silico breeding optimization. Since the accuracy and sensitivity of population simulation is critical to the quality of the output of the applications that use them, accurate algorithms are required to provide a strong foundation to the methods in these studies. RESULTS: In this paper we present SimBA (Simulation using Best-fit Algorithm) a non-generative approach, based on a combination of stochastic techniques and discrete methods. We optimize a hill climbing algorithm and extend the framework to include multiple subpopulation structures. Additionally, we show that SimBA is very sensitive to the input specifications, i.e., very similar but distinct input characteristics result in distinct outputs with high fidelity to the specified distributions. This property of the simulation is not explicitly modeled or studied by previous methods. CONCLUSIONS: We show that SimBA outperforms the existing population simulation methods, both in terms of accuracy as well as time-efficiency. Not only does it construct populations that meet the input specifications more stringently than other published methods, SimBA is also easy to use. It does not require explicit parameter adaptations or calibrations. Also, it can work with input specified as distributions, without an exemplar matrix or population as required by some methods. SimBA is available at http://researcher.ibm.com/project/5669 .

MOTIVATION: Recent advances in sequencing technology have resulted in the dramatic increase of sequencing data, which, in turn, requires efficient management of computational resources, such as computing time, memory requirements as well as prototyping of computational pipelines. RESULTS: We present GenomicTools, a flexible computational platform, comprising both a command-line set of tools and a C++ API, for the analysis and manipulation of high-throughput sequencing data such as DNA-seq, RNA-seq, ChIP-seq and MethylC-seq. GenomicTools implements a variety of mathematical operations between sets of genomic regions thereby enabling the prototyping of computational pipelines that can address a wide spectrum of tasks ranging from pre-processing and quality control to meta-analyses. Additionally, the GenomicTools platform is designed to analyze large datasets of any size by minimizing memory requirements. In practical applications, where comparable, GenomicTools outperforms existing tools in terms of both time and memory usage. AVAILABILITY: The GenomicTools platform (version 2.0.0) was implemented in C++. The source code, documentation, user manual, example datasets and scripts are available online at http://code.google.com/p/ibm-cbc-genomic-tools.

BACKGROUND: Modern high-throughput measurement technologies such as DNA microarrays and next generation sequencers produce extensive datasets. With large datasets the emphasis has been moving from traditional statistical tests to new data mining methods that are capable of detecting complex patterns, such as clusters, regulatory networks, or time series periodicity. Study of periodic gene expression is an interesting research question that also is a good example of challenges involved in the analysis of high-throughput data in general. Unlike for classical statistical tests, the distribution of test statistic for data mining methods cannot be derived analytically. RESULTS: We describe the randomization based approach to significance testing, and show how it can be applied to detect periodically expressed genes. We present four randomization methods, three of which have previously been used for gene cycle data. We propose a new method for testing significance of periodicity in gene expression short time series data, such as from gene cycle and circadian clock studies. We argue that the underlying assumptions behind existing significance testing approaches are problematic and some of them unrealistic. We analyze the theoretical properties of the existing and proposed methods, showing how our method can be robustly used to detect genes with exceptionally high periodicity. We also demonstrate the large differences in the number of significant results depending on the chosen randomization methods and parameters of the testing framework.By reanalyzing gene cycle data from various sources, we show how previous estimates on the number of gene cycle controlled genes are not supported by the data. Our randomization approach combined with widely adopted Benjamini-Hochberg multiple testing method yields better predictive power and produces more accurate null distributions than previous methods. CONCLUSIONS: Existing methods for testing significance of periodic gene expression patterns are simplistic and optimistic. Our testing framework allows strict levels of statistical significance with more realistic underlying assumptions, without losing predictive power. As DNA microarrays have now become mainstream and new high-throughput methods are rapidly being adopted, we argue that not only there will be need for data mining methods capable of coping with immense datasets, but there will also be need for solid methods for significance testing.

Randomization is an important technique for assessing the significance of data mining results. Given an input data set, a randomization method samples at random from some class of datasets that share certain characteristics with the original data. The measure of interest on the original data is then compared to the measure on the samples to assess its significance. For certain types of data, e.g., gene expression matrices, it is useful to be able to sample datasets that share row and column means and variances. Testing whether the results of a data mining algorithm on such randomized datasets differ from the results on the true dataset tells us whether the results on the true data were an artifact of the row and column means and variances, or due to some more interesting phenomena in the data. In this paper, we study the problem of generating such randomized datasets. We describe three alternative algorithms based on local transformations and Metropolis sampling, and show that the methods are efficient and usable in practice. We evaluate the performance of the methods both on real and generated data. The results indicate that the methods work efficiently and solve the defined problem.

BACKGROUND: Event sequences where different types of events often occur close together arise, e.g., when studying potential transcription factor binding sites (TFBS, events) of certain transcription factors (TF, types) in a DNA sequence. These events tend to occur in bursts: in some genomic regions there are more genes and therefore potentially more binding sites, while in some, possibly very long regions, hardly any events occur. Also some types of events may occur in the sequence more often than others. Tendencies of co-occurrence of binding sites of two or more TFs are interesting, as they may imply a co-operative role between the TFs in regulatory processes. Determining a numerical value to summarize the tendency for co-occurrence between two TFs can be done in a number of ways. However, testing for the significance of such values should be done with respect to a relevant null model that takes into account the global sequence structure. RESULTS: We extend the existing techniques that have been considered for determining the significance of co-occurrence patterns between a pair of event types under different null models. These models range from very simple ones to more complex models that take the burstiness of sequences into account. We evaluate the models and techniques on synthetic event sequences, and on real data consisting of potential transcription factor binding sites. CONCLUSION: We show that simple null models are poorly suited for bursty data, and they yield many false positives. More sophisticated models give better results in our experiments. We also demonstrate the effect of the window size, i.e., maximum co-occurrence distance, on the significance results.

BACKGROUND: There exist many segmentation techniques for genomic sequences, and the segmentations can also be based on many different biological features. We show how to evaluate and compare the quality of segmentations obtained by different techniques and alternative biological features. RESULTS: We apply randomization techniques for evaluating the quality of a given segmentation. Our example applications include isochore detection and the discovery of coding-noncoding structure. We obtain segmentations of relevant sequences by applying different techniques, and use alternative features to segment on. We show that some of the obtained segmentations are very similar to the underlying true segmentations, and this similarity is statistically significant. For some other segmentations, we show that equally good results are likely to appear by chance. CONCLUSION: We introduce a framework for evaluating segmentation quality, and demonstrate its use on two examples of segmental genomic structures. We transform the process of quality evaluation from simply viewing the segmentations, to obtaining p-values denoting significance of segmentation similarity.

Sequence segmentation and dimensionality reduction have been used as methods for studying high-dimensional sequences — they both reduce the complexity of the representation of the original data. In this paper we study the interplay of these two techniques. We formulate the problem of segmenting a sequence while modeling it with a basis of small size, thus essentially reducing the dimension of the input sequence. We give three different algorithms for this problem: all combine existing methods for sequence segmentation and dimensionality reduction. For two of the proposed algorithms we prove guarantees for the quality of the solutions obtained. We describe experimental results on synthetic and real datasets, including data on exchange rates and genomic sequences. Our experiments show that the algorithms indeed discover underlying structure in the data, including both segmental structure and interdependencies between the dimensions.

We study the problem of segmenting a sequence into k pieces so that the resulting segmentation satisfies monotonicity or unimodality constraints. Unimodal functions can be used to model phenomena in which a measured variable first increases to a certain level and then decreases. We combine a well-known unimodal regression algorithm with a simple dynamic-programming approach to obtain an optimal quadratic-time algorithm for the problem of unimodal k-segmentation. In addition, we describe a more efficient greedy-merging heuristic that is experimentally shown to give solutions very close to the optimal. As a concrete application of our algorithms, we describe two methods for testing if a sequence behaves unimodally or not. Our experimental evaluation shows that our algorithms and the proposed unimodality tests give very intuitive results.